UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
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If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
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Item 7.01. |
Regulation FD Disclosure. |
On June 11, 2021, CRISPR Therapeutics AG (the “Company”) and its partner Vertex Pharmaceuticals Incorporated (together with its affiliates, “Vertex”) issued a press release announcing new clinical data that is available at the European Hematology Association Annual Meeting from two ongoing Phase 1/2 open-label clinical trials of CTX001TM, an investigational CRISPR/Cas9 gene-editing therapy, in transfusion-dependent beta thalassemia, or TDT, and severe sickle cell disease, or SCD. A copy of the press release is attached hereto as Exhibit 99.1.
The information in this Item 7.01 of Form 8-K, including the accompanying Exhibit 99.1, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934 (the “Exchange Act”), or otherwise subject to the liability of such section, nor shall such information be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, regardless of the general incorporation language of such filing, except as shall be expressly set forth by specific reference in such filing.
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Item 8.01. |
Other Events |
On June 11, 2021, new clinical data from two ongoing Phase 1/2 open-label clinical trials of CTX001 in TDT (CLIMB THAL-111) and severe SCD (CLIMB SCD-121) were presented and are available as e-posters at the European Hematology Association Annual Meeting, or EHA. Copies of the poster presentations are attached hereto as Exhibit 99.2 and Exhibit 99.3 and are incorporated herein by reference.
The new clinical data on 22 patients, with follow-up of at least 3 months, and ranging from 4 months to 26 months, treated with CTX001 show a consistent and sustained response to treatment. In total, more than 40 patients have been dosed across both studies to date.
All 15 patients with TDT, including six who have the b0/b0 or other severe genotypes, were transfusion-free at last follow-up, and all seven patients with severe SCD were free of vaso-occlusive crises (VOCs) from CTX001 infusion through last follow-up. Five patients with TDT and two patients with SCD now have follow-up of greater than one year, demonstrating a stable and durable response to treatment. A summary of the results from the CLIMB-111 and CLIMB-121 Phase 1/2 clinical trials is provided below.
CLIMB-111 Trial in TDT: Updated Results
The 15 patients with TDT reported at EHA are patients who had reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy. All 15 patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin, fetal hemoglobin and transfusion independence.
All 15 patients were transfusion independent with follow-up ranging from 4 to 26 months after CTX001 infusion and had clinically meaningful improvements in total hemoglobin from 8.9 to 16.9 g/dL and fetal hemoglobin from 67.3% to 99.6% at last visit.
Bone marrow allelic editing data collected from 10 patients with at least 6 months of follow-up, of which five patients had at least 12 months of follow-up and one patient had at least 24 months of follow-up, demonstrated a durable effect.
The safety data from all 15 patients were generally consistent with an autologous stem cell transplant and myeloablative conditioning. As previously reported, there were four serious adverse events (SAEs) considered related or possibly related to CTX001 reported in one patient: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome. All four SAEs occurred in the context of HLH and have resolved. The majority of non-serious adverse events were considered mild to moderate.
The presentations at EHA and the data summarized in this press release cover all TDT patients dosed with CTX001 with three or more months of follow-up as of the data cut on March 30, 2021. In addition to the data presented above,
a TDT patient, with less than three months of follow-up and therefore not included in the data cut, experienced an SAE; this SAE of cerebellar hemorrhage, which was considered related to busulfan conditioning, has resolved.
Enrollment and dosing are ongoing.
CLIMB-121 Trial in Severe SCD: Updated Results
The seven patients reported at EHA are patients who had reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy. All seven patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin and fetal hemoglobin, as well as elimination of VOCs.
All seven patients remained VOC-free with follow-up ranging from five to 22 months after CTX001 infusion and had clinically meaningful improvements in total hemoglobin from 11 to 15.9 g/dL and fetal hemoglobin levels from 39.6% to 49.6% at last visit.
Bone marrow allelic editing data collected from four patients who have at least six months of follow-up, of which two had 12 months of follow-up, demonstrated a durable effect.
The safety data from all seven patients were generally consistent with an autologous stem cell transplant and myeloablative conditioning. There were no SAEs considered related to CTX001, and the majority of non-serious adverse events were considered mild to moderate.
Enrollment and dosing are ongoing.
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Item 9.01 |
Financial Statements and Exhibits |
(d) Exhibits
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104 |
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Cover Page Interactive Data File (embedded within the Inline XBRL document) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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CRISPR THERAPEUTICS AG |
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Date: June 11, 2021 |
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/s/ Samarth Kulkarni |
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Samarth Kulkarni, Ph.D. |
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Chief Executive Officer |
Exhibit 99.1
Vertex and CRISPR Therapeutics Present New Data in 22 Patients With Greater Than 3 Months Follow-Up Post-Treatment With Investigational CRISPR/Cas9 Gene-Editing Therapy, CTX001™ at European Hematology Association Annual Meeting
- Beta thalassemia: All 15 patients were transfusion independent after CTX001 infusion -
- Sickle cell disease: All seven patients were free of vaso-occlusive crises after CTX001 infusion -
BOSTON, Mass. and ZUG, Switzerland and CAMBRIDGE, Mass., June 11, 2021 -- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and CRISPR Therapeutics (Nasdaq: CRSP) today announced new data on 22 patients, with follow-up of at least 3 months, and ranging from 4 months to 26 months, treated with the investigational CRISPR/Cas9-based gene-editing therapy, CTX001, that show a consistent and sustained response to treatment. CTX001 is being investigated in two ongoing Phase 1/2 clinical trials as a potential one-time therapy for patients suffering from transfusion-dependent beta thalassemia (TDT) and severe sickle cell disease (SCD). In total, more than 40 patients have been dosed across both studies to date.
All 15 patients with TDT, including six who have the b0/b0 or other severe genotypes, were transfusion-free at last follow-up, and all seven patients with severe SCD were free of vaso-occlusive crises (VOCs) from CTX001 infusion through last follow-up. Five patients with TDT and two patients with SCD now have follow-up of greater than one year, demonstrating a stable and durable response to treatment. These data are available as e-posters beginning on June 11, 2021, at 09:00 CEST, and a partial presentation of these data were presented during the Joint EHA-ASH Symposium on June 10, 2021 from 17:30-18:30 CEST. A summary of the results from the CLIMB-111 and CLIMB-121 Phase 1/2 clinical trials is provided below.
“The data presented today in twenty-two patients are impressive in both the consistency and durability of effect. These results add to the growing body of evidence that CTX001 may hold the promise for a one-time functional cure for sickle cell disease and beta thalassemia. We are working with urgency to complete enrollment and look forward to finalizing regulatory discussions and moving towards filing,” said Reshma Kewalramani, M.D., Chief Executive Officer and President at Vertex.
“The continued progress and momentum of CTX001 validate the role that CRISPR gene-editing technology could have in the future of therapeutics,” added Samarth Kulkarni, Ph.D., Chief Executive Officer at CRISPR Therapeutics. “We are excited about these results and look forward to additional longer-term data and to moving this investigational medicine forward for a larger population of patients with these two devastating diseases.”
“As a physician caring for patients suffering from beta thalassemia, I have a high sense of urgency for novel and efficacious treatments,” said Dr. Franco Locatelli, Professor of Pediatrics at the Sapienza University of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. “These results suggest the potential for a durable benefit for patients with transfusion-dependent beta thalassemia.”
“It is thrilling to work on a groundbreaking program like CTX001,” said Dr. Stephan Grupp, Section Chief, Cellular Therapy and Transplant, Division of Oncology, Children's Hospital of Philadelphia. “This approach uses CRISPR/Cas9 gene editing to enable the patient’s own cells to produce fetal hemoglobin, and to see results that demonstrate the potential for a treatment that may transform the lives of many patients is an exciting time for me and the team.”
CLIMB-111 Trial in TDT: Updated Results
The 15 patients with TDT reported at EHA are patients who had reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy. All 15 patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin, fetal hemoglobin and transfusion independence.
All 15 patients were transfusion independent with follow-up ranging from 4 to 26 months after CTX001 infusion and had clinically meaningful improvements in total hemoglobin from 8.9 to 16.9 g/dL and fetal hemoglobin from 67.3% to 99.6% at last visit.
Bone marrow allelic editing data collected from 10 patients with at least 6 months of follow-up, of which five patients had at least 12 months of follow-up and one patient had at least 24 months of follow-up, demonstrated a durable effect.
The safety data from all 15 patients were generally consistent with an autologous stem cell transplant and myeloablative conditioning. As previously reported, there were four serious adverse events (SAEs) considered related or possibly related to CTX001 reported in one patient: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome. All four SAEs occurred in the context of HLH and have resolved. The majority of non-serious adverse events were considered mild to moderate.
The presentations at EHA and the data summarized in this press release cover all TDT patients dosed with CTX001 with three or more months of follow-up as of the data cut on March 30, 2021. In addition to the data presented above, a TDT patient, with less than three months of follow-up and therefore not included in the data cut, experienced an SAE; this SAE of cerebellar hemorrhage, which was considered related to busulfan conditioning, has resolved.
Enrollment and dosing are ongoing.
CLIMB-121 Trial in Severe SCD: Updated Results
The seven patients reported at EHA are patients who had reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy. All seven patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin and fetal hemoglobin, as well as elimination of VOCs.
All seven patients remained VOC-free with follow-up ranging from five to 22 months after CTX001 infusion and had clinically meaningful improvements in total hemoglobin from 11 to 15.9 g/dL and fetal hemoglobin levels from 39.6% to 49.6% at last visit.
Bone marrow allelic editing data collected from four patients who have at least six months of follow-up, of which two had 12 months of follow-up, demonstrated a durable effect.
The safety data from all seven patients were generally consistent with an autologous stem cell transplant and myeloablative conditioning. There were no SAEs considered related to CTX001, and the majority of non-serious adverse events were considered mild to moderate.
Enrollment and dosing are ongoing.
About CTX001
CTX001 is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD, in which a patient’s hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is a form of the oxygen-carrying hemoglobin that is naturally present at birth, which then switches to the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate or eliminate transfusion requirements for patients with TDT and reduce or eliminate painful and debilitating sickle crises for patients with SCD. Earlier results from these ongoing trials were published as a Brief Report in The New England Journal of Medicine in January of 2021.
Based on progress in this program to date, CTX001 has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration (FDA) for both TDT and SCD. CTX001 has also been granted Orphan Drug Designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both TDT and SCD.
Among gene-editing approaches being investigated/evaluated for TDT and SCD, CTX001 is the furthest advanced in clinical development.
About CLIMB-111
The ongoing Phase 1/2 open-label trial, CLIMB-Thal-111, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with TDT. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.
About CLIMB-121
The ongoing Phase 1/2 open-label trial, CLIMB-SCD-121, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with severe SCD. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.
This is a long-term, open-label trial to evaluate the safety and efficacy of CTX001 in patients who received CTX001 in CLIMB-111 or CLIMB-121. The trial is designed to follow participants for up to 15 years after CTX001 infusion.
About the Gene-Editing Process in These Trials
Patients who enroll in these trials will have their own hematopoietic stem and progenitor cells collected from peripheral blood. The patient’s cells will be edited using the CRISPR/Cas9 technology. The edited cells, CTX001, will then be infused back into the patient as part of a stem cell transplant, a process which involves, among other things, a patient being treated with myeloablative busulfan conditioning. Patients undergoing stem cell transplants may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of CTX001. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of CTX001 on multiple measures of disease and for safety.
About the Vertex-CRISPR Collaboration
Vertex and CRISPR Therapeutics entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CTX001 represents the first potential treatment to emerge from the joint research program. Under a recently amended collaboration agreement, Vertex will lead global development, manufacturing and commercialization of CTX001 and split program costs and profits worldwide 60/40 with CRISPR Therapeutics.
About Vertex
Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) — a rare, life-threatening genetic disease — and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of cell and genetic therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.
Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign. For company updates and to learn more about Vertex's history of innovation, visit www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.
Vertex Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Dr. Reshma Kewalramani, Dr. Samarth Kulkarni, Dr. Franco Locatelli, and Dr. Stephan Grupp, and statements regarding expectations that data will be presented and available as e-posters beginning on June 11, 2021, the potential benefits of CTX001, the potential benefits of our collaboration with CRISPR and CRISPR gene-editing technology, our plans and expectations for our clinical trials, including our expectations for the gene-editing process in these clinical trials, the status of our clinical trials of our product candidates under development by us and our collaborators, including activities at the clinical trial sites and patient enrollment, our expectations and plans regarding our regulatory discussions and future regulatory filings, and our expectations regarding the future activities of the parties pursuant to the amended collaboration agreement with CRISPR. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from a limited number of patients may not be indicative of final clinical trial results, that data from the company's development programs, including its programs with its collaborators, may not support registration or further development of its compounds due to safety and/or efficacy, or other reasons, that the COVID-19 pandemic may impact the status or progress of our clinical trials and clinical trial sites and the clinical trials and clinical trial sites of our collaborators, including patient enrollment, or other reasons, and other risks listed under the heading “Risk Factors” in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at www.sec.gov and available through the company's website at www.vrtx.com. You should not place undue reliance on these statements or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
About CRISPR Therapeutics
CRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic collaborations with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit www.crisprtx.com.
CRISPR THERAPEUTICS® word mark and design logo and CTX001™ are trademarks and registered trademarks of CRISPR Therapeutics AG. All other trademarks and registered trademarks are the property of their respective owners.
CRISPR Therapeutics Forward-Looking Statement
This press release may contain a number of “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements made by Dr. Reshma Kewalramani, Dr. Samarth Kulkarni, Dr. Franco Locatelli, and Dr. Stephan Grupp in this press release, as well as statements regarding CRISPR Therapeutics’ expectations about any or all of the following: (i) the safety, efficacy and clinical progress of CRISPR Therapeutics’ various clinical programs, including CTX001, including expectations regarding the data presented and available as e-posters beginning on June 11, 2021 and a partial presentation of such data during the Joint EHA-ASH Symposium on June 10, 2021; (ii) the potential and expected benefits of CRISPR Therapeutics’ collaboration with Vertex; and (iii) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words “believes,” “anticipates,” “plans,” “expects” and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, existing and prospective investors are cautioned that forward-looking statements are inherently uncertain, are neither promises nor guarantees and not to place undue reliance on such statements, which speak only as of the date they are made. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the potential for initial and preliminary data from any clinical trial and initial data from a limited number of patients (as is the case with CTX001 at this time) not to be indicative of final or future trial results; the potential that CTX001 clinical trial results may not be favorable or may not support registration or further development; the potential that future competitive or other market factors may adversely affect the commercial potential for CTX001; CRISPR Therapeutics may not realize the potential benefits of the collaboration with Vertex; potential impacts due to the coronavirus pandemic, such as to the timing and progress of clinical trials; uncertainties regarding the intellectual property protection for CRISPR Therapeutics’ technology and intellectual property belonging to third parties; and those risks and uncertainties described under the heading “Risk Factors” in CRISPR Therapeutics’ most recent annual report on Form 10-K, quarterly report on Form 10-Q, and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at www.sec.gov. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law.
Vertex Pharmaceuticals Incorporated
Investors:
Michael Partridge, +1 617-341-6108
or
Brenda Eustace, +1 617-341-6187
or
Manisha Pai, +1 617-429-6891
Media:
mediainfo@vrtx.com
or
U.S.: +1 617-341-6992
or
Heather Nichols: +1 617-839-3607
or
International: +44 20 3204 5275
CRISPR Therapeutics
Investors:
Susan Kim, +1 617-307-7503
susan.kim@crisprtx.com
Media:
Rachel Eides, +1-617-315-4493
Rachel.Eides@crisprtx.com
Connecting Hematology For Clinical and Research Excellence VIRTUAL June 9 - 17, 2021 EHA 2021 CTX001™ for Sickle Cell Disease: Safety and Efficacy Results from the Ongoing CLIMB SCD-121 Study of Autologous CRISPR-Cas9-Modified CD34+ Hematopoietic Stem and Progenitor Cells S. GRUPP1, N. BLOBERGER2, C. CAMPBELL3, C. CARROLL4, J.S. HANKINS5, T.W. HO2, W. HOBBS3, S. IMREN3, Y. LU3, M. MAPARA6, M. DE MONTALEMBERT7, L. MORITZ3, D. RONDELLI8, N. SHANBHAG3, A. SHARMA5, P. SRIPAKDEEVONG2, M.H. STEINBERG9, H. FRANGOUL4 1Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA | 2CRISPR Therapeutics, Cambridge, MA, USA | 3Vertex Pharmaceuticals Incorporated, Boston, MA, USA | 4Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, TN, USA | 5St. Jude Children’s Research Hospital, Memphis, TN, USA | 6Columbia University, New York, NY, USA | 7Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), University of Paris, Paris, France | 8University of Illinois at Chicago, Chicago, IL, USA | 9Boston University School of Medicine, Boston, MA, USA INTRODUCTION In patients with sickle cell disease (SCD), a reduction in the level of fetal hemoglobin (HbF) shortly after birth is associated with the onset of symptoms1 Naturally occurring genetic polymorphisms in BCL11A, a repressor of HbF, are associated with elevated HbF and decreased severity of SCD2,3 Editing of BCL11A results in reactivation of γ-globin expression and formation of HbF (α2γ2) in animal models3,4 CTX001™ is a genetically modified cell therapy that uses non-viral, ex vivo CRISPR-Cas9 gene editing in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid enhancer region of the BCL11A gene to reduce expression of BCL11A and reactivate HbF production5 Early results from the Phase 1/2 CLIMB SCD-121 study of patients with SCD and the Phase 1/2 CLIMB THAL-111 study of patients with transfusion-dependent β-thalassemia (TDT) infused with CTX001 demonstrate clinically meaningful increases in total hemoglobin (Hb) and HbF that occurred early and were maintained over time, and a safety profile generally consistent with myeloablative conditioning. Elimination of vaso-occlusive crises (VOCs) in patients with SCD infused with CTX001 and elimination of transfusion requirements within 2 months of CTX001 infusion in patients with TDT were also observed6 OBJECTIVE To present updated data from the CLIMB SCD-121 study for patients (N=7) with >3 months of follow-up after CTX001 infusion from a data cut on 15 March 2021. As of 26 May 2021, a total of .40 patients with SCD and TDT have been dosed with CTX001 METHODS Study Design and Patient Population CLIMB SCD-121 (NCT03745287) is a Phase 1/2, international, multicenter, open-label, single-arm study investigating the safety and efficacy of autologous CD34+ CRISPR-Cas9- modified HSPCs (CTX001) in patients with SCD Patients aged 12 to 35 years with severe SCD, defined as a history of >2 VOCs per year in the previous 2 years, were eligible CTX001 Manufacturing and Infusion (Figure 1) CD34+ HSPCs were collected from patients by apheresis following mobilization with plerixafor CTX001 was manufactured from these CD34+ cells by editing at the erythroid enhancer region of BCL11A with a specific single-guide RNA and Cas9 nuclease Patients received myeloablative conditioning with pharmacokinetically adjusted busulfan followed by a one-time infusion of CTX001 Patients were monitored for engraftment, hematopoietic recovery, adverse events (AEs), Hb production, hemolysis, HbF and F-cell expression, and number of VOCs occurring during follow-up Bone marrow aspirates were obtained at 6 and 12 months after CTX001 infusion and next-generation sequencing was used to measure the fraction of on-target allelic editing in CD34+ bone marrow cells Safety The safety profile of CTX001 is generally consistent with myeloablation and autologous hematopoietic stem cell transplant As previously reported, post-CTX001 infusion, 1 patient experienced a serious AE (SAE) related to busulfan: sepsis; resolved6 No SAEs related to CTX001 were reported Efficacy Increases in total Hb and HbF occurred early and were maintained over time; mean %HbF increased to .30% by 3 months following infusion (Figure 2) Pancellular expression of HbF following CTX001 infusion demonstrates homogenous distribution of HbF – The mean proportion of circulating red blood cells expressing HbF (F-cells) increased to .95% (Figure 3) All 7 patients have remained VOC-free from CTX001 infusion to time of this analysis, with up to 22.4 months of total follow-up (Figure 4) CONCLUSIONS All patients (N=7) have been VOC-free from the time of CTX001 infusion, with a follow-up of 4.9 to 22.4 months The safety profile of CTX001 is generally consistent with that of myeloablative conditioning and autologous hematopoietic stem cell transplant All patients demonstrated clinically meaningful increases in total Hb and HbF which occurred early and have been maintained over time After CTX001 infusion, high levels of BCL11A edited alleles in CD34+ bone marrow cells were maintained The updated data reported here are consistent with previous reports and support continued investigation of CTX001 as a potential functional cure for patients with SCD Hemolysis Improvements in markers of hemolysis (serum lactate dehydrogenase and haptoglobin) were observed. Haptoglobin was detectable by Month 6 in all 4 patients with Month 6 values Durable BCL11A Editing Observed in CD34+ Bone Marrow Cells Bone marrow editing assessments were performed starting at 6 months and 12 months of follow-up The mean proportion of edited alleles in CD34+ bone marrow cells was 85.5% (range: 80.4% to 93.1%) in the 4 patients with data available at 6 months post CTX001 infusion In the 2 patients with at least 12 months of follow-up post CTX001 infusion, the proportion of edited alleles was maintained in bone marrow cells over the duration of follow-up (in the first patient, 81.4% and 80.4% at Months 6 and 12, respectively [22.4 months of total follow-up]; and in the second patient, 87.3% and 87.1% at Months 6 and 12, respectively [13.6 months of total follow-up]) ACKNOWLEDGMENTS The authors and sponsors would like to thank the study participants and their families, as well as sites, investigators, nurses, and the entire CTX001 team from CRISPR Therapeutics and Vertex Pharmaceuticals. Medical writing support was provided by Joseph C.P. Kruempel, PhD and Katie L. Beski, PhD of Complete HealthVizion, Inc., Chicago, IL, USA, funded by Vertex Pharmaceuticals Incorporated. Development and review coordination was provided by Kevin Clarke, PharmD, RPh, of Vertex Pharmaceuticals Incorporated, who holds stock and/or stock options in that company. REFERENCES Sankaran VG, et al. Cold Spring Harb Perspect Med. 2013;3:a01164. Uda M, et al. Proc Natl Acad Sci U S A. 2008;105:1620-1625. 3. Bauer DE, et al. Science. 2013;342:253-257. Demirci S, et al. J Clin Invest. 2020;130:6677-6687. Frangoul H, et al. N Engl J Med. 2021;384:252-260. Frangoul H, et al. Poster presented at the 62nd Annual American Society of Hematology Meeting 2020. AUTHOR DISCLOSURES This study was sponsored by Vertex Pharmaceuticals Incorporated and CRISPR Therapeutics AG. SG has received grants from Novartis, Kite, Servier, Jazz, and Vertex/CRISPR; consults for Novartis, Roche, GSK, Cure Genetics, Humanigen, CBMG, Janssen/JnJ, and Jazz; is on the advisory boards/steering committees for Adaptimmune, TCR2, Cellectis, Juno, Vertex/CRISPR, and Allogene; and has patent Toxicity management for anti-tumor activity of CARs, WO 2014011984 A1 licensed to the University of Pennsylvania. NB, TWH, and PS are employees of CRISPR Therapeutics and hold stock/stock options. C Campbell, WH, SI, YL, LM, and NS are employees of Vertex Pharmaceuticals Incorporated and hold stock/stock options. JSH has received consulting fees from bluebird bio. M de Montalembert is on the advisory boards for Addmedica, bluebird bio, and Novartis. DR is on the advisory board for Vertex. AS is a consultant for Spotlight Therapeutics and Medexus Inc., and has received research funding from CRISPR Therapeutics AG. MHS is on the advisory boards for Vertex/ CRISPR, Fulcrum Therapeutics, DSMB, and Imara. HF is on the study Data and Safety Monitoring Board for Rocket Pharma and the steering committee for CTX001-121. C Carroll and M Mapara have nothing to declare. RESULTS Table 1. Patient Baseline Demographics and Treatment Characteristics Patient Demographics, N=7 Genotype, n βs/βs 7 Gender, n Female/male 3/4 Age in years, median (range) 22 (19–34) Pre-study VOCsa VOCs per year, median (range) 5.5 (2.5–9.5) Treatment Characteristics, N=7 Median (Range) Drug product cell dose, CD34+ cells 106/kg3.3 (3.1–3.9) Neutrophil engraftmentb, Study Dayc25 (17–33) Platelet engraftmentd, Study Dayc33 (30–53) Duration of follow-up, months7.6 (4.9–22.4) VOCs, vaso-occlusive crises. aAnnualized rate during the 2 years before consenting to study participation; bDefined as the first day of 3 measurements of absolute neutrophil count >500 cells/µL on 3 consecutive days; cStudy Day 1 is the day of CTX001 infusion; dDefined as the first day of 3 consecutive measurements of platelet count >50,000/µL on 3 different days after CTX001 infusion, without a platelet transfusion in the past 7 days. Table 2. Summary of Adverse Events Months of follow-up, median (range) 7.6 (4.9–22.4) Patients with non-serious AEs, n Patients with SAEs, n Relationshipa Related to plerixafor Related to busulfan only Related to CTX001 only Related to busulfan and CTX001 6 7 0 3b 2 1 0 0 Total Hb, 7.7 Mean (range), g/dL (5.7–9.7) 9.5 (8.0–12.5) 11.2 (8.9–13.7) 12.1 (10.0–15.4) 12.5 13.2 (9.7–14.9)(11.7–16.1) 13.5 (11.3–15.9) 11.3 (10.7–11.8) 10.7 (10.3–11.0) 12.0 11.4 12.0 %HbF, Mean (range) Baseline 1 2 3 456 Months after CTX001 Infusion 9 12 15 18 21 N= 7 CTX001 Infusion Mean Hb fractionation, Hb g/dL 7 7 7 765 2 2 1 1 1 HbF HbS HbA HbA2 27.1%37.4%44.2%45.9%45.3%48.2%46.0% (21.1–33.7) (31.3–46.8) (39.6–49.5) (40.6–50.9) (41.9–48.0) (46.1–50.2) (42.4–49.6) 43.2% 43.1% 42.0% 5.7% (0.8–17.3) 4.0% (0.0–9.1) Hb, hemoglobin; HbA, adult hemoglobin; HbF, fetal hemoglobin; HbS, sickle hemoglobin. Bars show mean Hb in g/dL, labels indicate mean proportion of HbF as a percentage of total Hb. Figure 2. All Patients Demonstrated Increased Total Hb and HbF 13.6 9.6 7.5 6.3 5.6 4.9 17.0 Total Hb at last visit Pre-study VOC burden Average number per year over the Patient previous 2 years 4.0 024681012141618202224 Months after CTX001 Infusion 7 9.5 6 5.5 5 2.5 4 4.0 3 7.5 22.412.0 g/dL 12.5 g/dL 11.7 g/dL 15.2 g/dL 15.9 g/dL 13.7 g/dL 11.0 g/dL 2 Patient not experiencing VOCs Hb, hemoglobin; VOC, vaso-occlusive crisis. Figure 4. All Patients Infused with CTX001 Remain VOC-Free 19.8 (7.9–33.9) 11.7 (4.3–33.5) 49.0 (34.0–61.0) 74.7 (64.6–91.5) (85.4–98.1) 96.396.2 97.897.5 93.0 (94.6–99.9) (91.9–99.6) (92.7–99.7) (95.7–99.2) 98.1 98.1 98.1 CTX001 Infusion Baseline 1 2 345 N= 7 7 7 Months afte 764 6 r CTX001 Infusion 4 9 12 15 18 21 2 2 1 1 1 Mean (range) % peripheral F-cells, % circulating RBCs expressing HbF F-cells, HbF- containing cells; HbF, fetal hemoglobin; RBCs, red blood cells. Figure 3. Pancellular Expression of HbF is Maintained 5. Figure adapted from Frangoul H, et al. N Engl J Med. 2021;384:252-260. QC, quality control. aPatients enrolled in CLIMB SCD-121 received plerixafor only. Back-up cells kept at site as a safety measure; bPatients will be followed for 24 months after CTX001 infusion with physical exams, laboratory and imaging assessments, and adverse event evaluations; cAll patients who receive CTX001 will be followed for 15 years overall in a long-term follow-up study (NCT04208529) after completion or withdrawal from CLIMB SCD-121. Figure 1. CTX001 Infusion Process5 Stage 1Stage 2Stage 3 Stage 4 ScreeningStem cellsand ready collectedafor infusion Clinical trial siteMyeloablative Cells returned conditioning (busulfan)CTX001 infusion Not related to any study drug76 AEs, adverse events; SAEs, serious adverse events. aIncludes related, possibly related, and missing relationship AEs; b3 patients experienced non-serious AEs related or possibly related to busulfan and CTX001: dermatitis, lymphopenia, and CD4 lymphocytes decreased. Discharge and 2-year follow-upb Engraftment andLong-term hematopoieticfollow-upc recovery Cells frozen and undergo QC testing before release Central manufacturing location Cells shipped to a central manufacturing location CRISPR-Cas9 editing Isolate CD34+ cells Exhibit 99.2
Connecting Hematology For Clinical and Research Excellence VIRTUAL June 9 - 17, 2021 EHA 2021 CTX001™ for Transfusion-Dependent β-Thalassemia: Safety and Efficacy Results from the Ongoing CLIMB THAL-111 Study of Autologous CRISPR-Cas9-Modified CD34+ Hematopoietic Stem and Progenitor Cells F. LOCATELLI1, S. AILINCA-LUCHIAN2, Y. BOBRUFF2, M. DOMENICA CAPPELLINI3, S. CORBACIOGLU4, J. DOMM5, J. FOELL4, J. DE LA FUENTE6, R. HANDGRETINGER7, T.W. HO2, W. HOBBS8, A. KATTAMIS9, A. LI10, Y. LU8, L. PALOMINO2, N. SHANBHAG8, A. SHARMA2, S. SHETH11, P. SRIPAKDEEVONG2, D. WALL12, H. FRANGOUL5 1Ospedale Pediatrico Bambino Gesù Rome, Sapienza, University of Rome, Rome, Italy | 2CRISPR Therapeutics, Cambridge, MA, USA | 3University of Milan, Milan, Italy | 4University of Regensburg, Regensburg, Germany | 5Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, TN, USA | 6Imperial College Healthcare NHS Trust, St Mary’s Hospital, London, UK | 7Children’s University Hospital, University of Tübingen, Tübingen, Germany | 8Vertex Pharmaceuticals Incorporated, Boston, MA, USA | 9University of Athens, Athens, Greece | 10BC Children’s Hospital, University of British Columbia, Vancouver, Canada | 11Joan and Sanford I Weill Medical College of Cornell University, New York, NY, USA | 12The Hospital for Sick Children/University of Toronto, Toronto, Canada INTRODUCTION In patients with transfusion-dependent β-thalassemia (TDT), a reduction in the level of fetal hemoglobin (HbF) shortly after birth is associated with the onset of symptoms and transfusion dependence1 Naturally occurring genetic polymorphisms in BCL11A, a repressor of HbF, are associated with elevated HbF and decreased severity of TDT2,3 Editing of BCL11A results in reactivation of γ-globin expression and formation of HbF (α2γ2) in animal models3,4 CTX001™ is a genetically modified cell therapy that uses non-viral, ex vivo CRISPR-Cas9 gene editing in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid enhancer region of the BCL11A gene to reduce expression of BCL11A and reactivate HbF production5 Early results from the Phase 1/2 CLIMB THAL-111 study of patients with TDT and the Phase 1/2 CLIMB SCD-121 study of patients with sickle cell disease (SCD) infused with CTX001 demonstrate clinically meaningful increases in total hemoglobin (Hb) and HbF that occurred early and were maintained over time, and a safety profile generally consistent with myeloablative conditioning. Elimination of transfusion requirements within 2 months of CTX001 infusion in patients with TDT and elimination of vaso-occlusive crises in patients with SCD were also observed6 OBJECTIVE To present updated data from the CLIMB THAL-111 study for patients (N=15) with >3 months of follow-up after CTX001 infusion from a data cut on 30 March 2021. As of 26 May 2021, a total of .40 patients with SCD and TDT have been dosed with CTX001 METHODS Study Design and Patient Population CLIMB THAL-111 (NCT03655678) is a Phase 1/2, international, multicenter, open-label, single-arm study investigating the safety and efficacy of autologous CD34+ CRISPR-Cas9- modified HSPCs (CTX001) in patients with TDT Patients aged 12 to 35 years with a diagnosis of TDT, defined as a history of >100 mL/kg/ year or >10 units/year of packed red blood cell (pRBC) transfusions in the previous 2 years, were eligible CTX001 Manufacturing and Infusion (Figure 1) CD34+ HSPCs were collected from patients by apheresis following mobilization with filgrastim and plerixafor + CTX001 was manufactured from these CD34 cells by editing at the erythroid enhancer region of BCL11A with a specific single-guide RNA and Cas9 nuclease Patients received myeloablative conditioning with pharmacokinetically adjusted busulfan followed by a one-time infusion of CTX001 Patients were monitored for engraftment, hematopoietic recovery, adverse events (AEs), Hb production, HbF and F-cell expression, and pRBC transfusion requirements occurring during follow-up Bone marrow aspirates were obtained at 6, 12, and 24 months after CTX001 infusion and next-generation sequencing was used to measure the fraction of on-target allelic editing in CD34+ bone marrow cells The safety profile of CTX001 is generally consistent with myeloablation and autologous hematopoietic stem cell transplant As previously reported, 1 patient had 4 serious AEs (SAEs) assessed by the investigator as related or possibly related to CTX001: headache, haemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome (latter also related to busulfan), all in the context of HLH6 3 patients experienced SAEs assessed as related or possibly related to busulfan only: venoocclusive liver disease (2 patients), febrile neutropenia (1 patient), colitis (1 patient), and pneumonia (1 patient). All were previously reported, except for the SAE of pneumonia All of these SAEs have resolved CONCLUSIONS All patients (N=15) stopped transfusions within 2 months of CTX001 infusion, with a follow-up of 4.0 to 26.2 months The safety profile of CTX001 is generally consistent with that of myeloablative conditioning and autologous hematopoietic stem cell transplant All patients demonstrated clinically meaningful increases in total Hb and HbF which occurred early and have been maintained over time After CTX001 infusion, high levels of BCL11A edited alleles in CD34+ bone marrow cells were maintained The updated data reported here are consistent with previous reports and support continued investigation of CTX001 as a potential functional cure for patients with TDT Durable BCL11A Editing Observed in CD34+ Bone Marrow Cells In the 10 patients with data available at 6 months post CTX001 infusion, the mean proportion of edited alleles in CD34+ bone marrow cells was 70.5% (range: 41.8% to 91.4%) at 6 months; in the 5 patients with at least 12 months of follow-up, the mean proportion of edited alleles in CD34+ bone marrow cells was 71.4% (range: 41.8% to 88.1%) at 6 months and 73.6% (range: 53.3% to 88.2%) at 12 months The proportion of edited alleles has been maintained in bone marrow cells over the duration of follow-up post CTX001 infusion (Figure 5) ACKNOWLEDGMENTS The authors and sponsors would like to thank the study participants and their families, as well as sites, investigators, nurses, and the entire CTX001 team from CRISPR Therapeutics and Vertex Pharmaceuticals. Medical writing support was provided by Katie L. Beski, PhD of Complete HealthVizion, Inc., Chicago, IL, USA, funded by Vertex Pharmaceuticals Incorporated. Development and review coordination was provided by Kevin Clarke, PharmD, RPh, of Vertex Pharmaceuticals Incorporated, who holds stock and/or stock options in that company. REFERENCES Sankaran VG, et al. Cold Spring Harb Perspect Med. 2013;3:a01164. Uda M, et al. Proc Natl Acad Sci U S A. 2008;105:1620-1625. 3. Bauer DE, et al. Science. 2013;342:253-257. Demirci S, et al. J Clin Invest. 2020;130:6677-6687. Frangoul H, et al. N Engl J Med. 2021;384:252-260. Frangoul H, et al. Poster presented at the 62nd Annual American Society of Hematology Meeting 2020. AUTHOR DISCLOSURES This study was sponsored by Vertex Pharmaceuticals Incorporated and CRISPR Therapeutics AG. S A-L, YB, TWH, LP, AS, and PS are employees of CRISPR Therapeutics and hold stock/stock options. MDC is on the advisory boards for Sanofi Genzyme, Novartis, BMS/Celgene, Vifor, CRISPR, and Silence. AL reports consultancy for Novartis Canada. J de la Fuente is on the advisory board for Jazz Pharmaceuticals. WH, YL, and NS are employees of Vertex Pharmaceuticals Incorporated and hold stock/stock options. AK has received grants from Novartis, personal fees from Novartis, Chiesi, BMS/Celgene, and Agios Pharmaceuticals, and is on the advisory boards for Vertex/CRISPR, BMS/Celgene, Ionis, and Vifor. SS has received grants from Agios, La Jolla, Terumo, DisperSol, Novartis, and Celgene, is a consultant for Agios, Celgene, bluebird bio, Acceleron, and Chiesi, and is on the steering committee for Vertex/CRISPR. HF is on the study Data and Safety Monitoring Board for Rocket Pharma and the steering committee for CTX001-121. FL, SC, J Foell, RH, JD, and DW have nothing to declare. RESULTS Table 1. Patient Baseline Demographics and Treatment Characteristics Patient Demographics, N=15 Genotype, n β0/β0 β0/IVS-I-110 IVS-I-110/IVS-I-110 β /β 0 E β0/β+ β+/β+ 2 2 2 2 4 3 Gender, n Female/male 9/6 Age in years, median (range) 23 (18–32) Pre-study pRBC transfusionsa Units per year, median (range) 34 (20.5–61) Treatment Characteristics, N=15 Median (Range) Drug product cell dose, CD34+ cells 106/kg6.5 (3.5–16.6) Neutrophil engraftmentb, Study Dayc29 (19–39) Platelet engraftmentd, Study Dayc40 (29–56) Duration of follow-up, months8.7 (4.0–26.2) pRBC, packed red blood cell. aAnnualized number during the 2 years before consenting to study participation; bDefined as the first day of 3 measurements of absolute neutrophil count >500 cells/µL on 3 consecutive days; cStudy Day 1 is the day of CTX001 infusion; dDefined as the first day of 3 consecutive measurements of platelet count >20,000/µL on 3 different days after CTX001 infusion, without a platelet transfusion in the past 7 days. Safety Table 2. Summary of Adverse Events Months of follow-up, median (range) 8.7 (4.0–26.2) Patients with non-serious AEs, n Patients with SAEs, n Relationshipa Related to plerixafor and/or G-CSF Related to busulfan only Related to CTX001 only Related to busulfan and CTX001 Not related to any study drug 10 15 1b 3c 15 0 3 1 1 9 AEs, adverse events; G-CSF, granulocyte colony-stimulating factor; SAEs, serious adverse events; WBC, white blood cell. aIncludes related, possibly related, and missing relationship AEs; b1 patient experienced a non-serious AE of anaemia possibly related to CTX001 (resolved); c3 patients experienced non-serious AEs related or possibly related to busulfan and CTX001: petechiae, pyrexia, epistaxis, lymphocyte count decreased, neutrophil count decreased, WBC count decreased, and platelet count decreased (all resolved). In addition to the safety data presented above, which includes all patients dosed with CTX001 with >3 months of follow-up as of the data cut of 30 March 2021, an additional SAE is included here, in a patient with 3 months of follow-up as of the data cut of 30 March 2021. This patient experienced an SAE of cerebellar hemorrhage, assessed by the investigator to be life-threatening, related to busulfan-induced thrombocytopenia, and not related to CTX001. The SAE has since resolved Stage 3 Stage 4 Clinical trial site ScreeningStem cells collecteda Myeloablative Cells returned conditioning and ready(busulfan) for infusion CTX001 infusion Discharge and 2-year follow-upb Engraftment andLong-term hematopoieticfollow-upc recovery Cells frozen and undergo QC testing before release Central manufacturing location Cells shipped to a central manufacturing location CRISPR-Cas9 editing Isolate CD34+ cells 5. Figure adapted from Frangoul H, et al. N Engl J Med 2021;384:252-260. QC, quality control. aPatients enrolled in CLIMB THAL-111 received a combination of plerixafor and filgrastim for mobilization. Back-up cells kept at site as a safety measure; bPatients will be followed for 24 months after CTX001 infusion with physical exams, laboratory and imaging assessments, and adverse event evaluations; cAll patients who receive CTX001 will be followed for 15 years overall in a long-term follow-up study (NCT04208529) after completion of or withdrawal from CLIMB THAL-111. Figure 1. CTX001 Infusion Process5 Stage 1Stage 2 11.6 (8.9–13.7) 12.0 CTX001 Infusion 11.011.4 (6.6–16.2) (8.5–17.6) 12.212.4 (9.7–17.2) (10.0–16.9) 12.1 (1 (9.9–13.5) 1.1–12.9) 13.2 (12.1–14.2) 14.1 13.3 4.77.510.310.810.311.011.512.613.112.5 (1.9–9.9) (4.0–10.4) (6.1–13.4) (7.4–13.2) (6.9–13.0) (9.1–12.9) (9.1–12.6) (11.7–13.5) 14.7 14.1 2345691215182124 Months after CTX001 Infusion Total Hb, 10.1 Mean (range), g/dL (7.2–13.7) HbF, 0.5 Mean (range), g/dL (0.0–1.9) N= 1515141414131165211 1 1 8.7 (4.6–13.2) 0.5 (0.1–1.8) Baseline Mean Hb fractionation, Hb g/dL HbFHbAHbA2 Hb, hemoglobin; HbA, adult hemoglobin; HbF, fetal hemoglobin. Efficacy Increases in total Hb and HbF occurred early and were maintained over time (Figure 2) Figure 2. All Patients Demonstrated Increased Total Hb and HbF +a Proportion of edited alleles in CD34 bone marrow cells , % 80.9 6-month visit 12-month visit 24-month visit Patient 1 78.1 Patient 2 41.8 Patient 3 72.6 Patient 4 76.6 Patient 5 88.1 76.1 53.3 69.5 81.0 88.2 aBone marrow editing assessments performed at 6 months, 12 months, and 24 months of follow-up. Figure 5. Durable BCL11A Editing Observed in CD34+ Bone Marrow Cells in Patients with >12 Months of Follow-Up 14.6 (5.3–46.6) 9.7 (2.6–27.5) 50.8 (8.8–75.8) 78.7 (43.9–92.2) 96.9 99.7 92.6 (82.0–100.0) (94.7–100.0) (96.5–100.0) (99.1–100.0) (96.9–100.0) (75.4–98.4) 98.798.698.5100.097.6100.0 Mean (range) % peripheral F-cells, % circulating RBCs expressing HbF CTX001 Infusion Baseline123456912151821 24 Months after CTX001 Infusion N= 15151514131110552111 F-cells, HbF-containing cells; HbF, fetal hemoglobin; RBCs, red blood cells. Pancellular expression of HbF following CTX001 infusion demonstrates homogenous distribution of HbF – The mean proportion of circulating RBCs expressing HbF (F-cells) increased to .95% (Figure 3) Figure 3. Pancellular Expression of HbF is Maintained 0246810 12 14 16 18 20 22 24 26 Months after CTX001 Infusion 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Genotype Pre-study RBC transfusions, units/year β0/β+ (IVS-I-110)a34.0 β0/β+ 61.0 β+/β+ 51.5 β0/β+ 23.5 β+/β+ 33.0 β0/β+ (IVS-I-110)a26.5 β0/β0 26.0 β0/βE 28.5 β0/β+ 35.0 IVS-I-110/IVS-I-110a44.5 β0/βE 20.5 IVS-I-110/IVS-I-110a 49.5 β0/β+ 39.5 β+/β+ 28.0 β0/β0 34.5 Total Hb at last visit 14.7 g/dL 12.1 g/dL 11.3 g/dL 12.6 g/dL 11.1 g/dL 12.8 g/dL g/dL g/dL 8.9 g/dL 12.7 g/dL 13.7 g/dL 13.0 g/dL 16.9 g/dL 12.4 g/dL 10.5 g/dL Patient receiving pRBC transfusionsPatient not receiving pRBC transfusions Patient 9.2 7.4 7.8 6.5 6.7 6.1 5.1 4.6 3.7 2.4 13.2 13.5 12.9 15.4 1.0 1.9 1.5 1.0 0.9 0.7 2.0 0.9 1.3 0.9 0.7 0.8 0.8 0.8 1.7 25.2 Hb, hemoglobin; pRBC, packed red blood cell; RBC, red blood cell. aThe IVS-I-110 phenotype is severe and similar to β0. All 15 patients were transfusion-free at the time of this analysis (within a median of 0.9 months after CTX001 infusion [range: 0.7 to 2.0 months]), with up to 26.2 months of total follow-up (Figure 4) Figure 4. Patients Have Stopped Receiving Transfusions Within 2 Months of CTX001 Infusion Exhibit 99.3